Cerivastatin improves survival of mice with lipopolysaccharide-induced sepsis

Development of severe sepsis is thought to result from the overproduction o f cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleuki n-1 beta (IL-1 beta), and nitric oxide. Recently, 3-hydroxy-3-methylglutary l coenzyme A reductase inhibitors, which are antihypercholesterolemic agent s, have been reported to inhibit lipopolysaccharide (LPS)-induced productio n of cytokines and nitric oxide in vitro. In this study, we tested these ef fects in vivo. After LPS administration (15 mg/kg i.p.) to CD-1 mice, serum levels of both TNF-alpha and IL-1 beta transiently increased, and peaked a t 2 h. After the peak responses of TNF-alpha and IL-1 beta, serum levels of nitrite and nitrate increased until at least 8 h. Pretreatment of the mice with cerivastatin (20 mg/kg i.p. 12 and 1 h before LPS injection) reduced serum levels of TNF-alpha and IL-1 beta at 2 h, and nitrite and nitrate at 8 h, by 93, 60, and 44%, respectively. In this model of sepsis, cerivastati n significantly (P = .016) improved the rate of 7-day survival from 26.7 to 73.3%. These results cast new light on the usefulness of cerivastatin in p reventing severe sepsis.